rs143136329

Variant names:

• chr10-71732339-C-G
• rs143136329
• NM_022124.6:c.4068C>G

Your query was ambiguous. Multiple possible variants found:

• chr10-71732339-C-G
• chr10-71732339-C-T
• chr10-71732339-C-A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_022124.6(CDH23):​c.4068C>G​(p.Thr1356Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,582,674 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1356T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0053 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00099 (9 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -0.103
• Publications: 1 publications found

Genes affected

CDH23 (HGNC:13733): (cadherin related 23) This gene is a member of the cadherin superfamily, whose genes encode calcium dependent cell-cell adhesion glycoproteins. The encoded protein is thought to be involved in stereocilia organization and hair bundle formation. The gene is located in a region containing the human deafness loci DFNB12 and USH1D. Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of this cadherin-like gene. Upregulation of this gene may also be associated with breast cancer. Alternative splice variants encoding different isoforms have been described. [provided by RefSeq, May 2013]

C10orf105 (HGNC:20304): (chromosome 10 open reading frame 105) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 10-71732339-C-G is Benign according to our data. Variant chr10-71732339-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45938.
• BP7: Synonymous conserved (PhyloP=-0.103 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00527 (803/152348) while in subpopulation AFR AF = 0.0159 (661/41582). AF 95% confidence interval is 0.0149. There are 8 homozygotes in GnomAd4. There are 395 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022124.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	NM_022124.6	MANE Select	c.4068C>G	p.Thr1356Thr	synonymous	Exon 32 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.4068C>G	p.Thr1356Thr	synonymous	Exon 32 of 32	NP_001165401.1	A0A087WYR8
	C10orf105	NM_001168390.2		c.-6+5389G>C		intron	N/A	NP_001161862.1	Q8TEF2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.4068C>G	p.Thr1356Thr	synonymous	Exon 32 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000616684.4	TSL:5	c.4068C>G	p.Thr1356Thr	synonymous	Exon 32 of 32	ENSP00000482036.2	A0A087WYR8
	CDH23	ENST00000398809.9	TSL:5	c.4065C>G	p.Thr1355Thr	synonymous	Exon 32 of 32	ENSP00000381789.5	A0A0A0MS94

Frequencies

GnomAD3 genomes AF: 0.00528 AC: 804 AN: 152230 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00226 AC: 445 AN: 196732 AF XY: 0.00200

Gnomad AFR exome AF: 0.0188

Gnomad AMR exome AF: 0.000603

Gnomad ASJ exome AF: 0.0169

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000542

Gnomad OTH exome AF: 0.00307

GnomAD4 exome AF: 0.000989 AC: 1414 AN: 1430326 Hom.: 9 Cov.: 33 AF XY: 0.000919 AC XY: 651 AN XY: 708760

African (AFR) AF: 0.0156 AC: 508 AN: 32648

American (AMR) AF: 0.000888 AC: 35 AN: 39408

Ashkenazi Jewish (ASJ) AF: 0.0151 AC: 386 AN: 25596

East Asian (EAS) AF: 0.00 AC: 0 AN: 37806

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82402

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51384

Middle Eastern (MID) AF: 0.00870 AC: 50 AN: 5744

European-Non Finnish (NFE) AF: 0.000245 AC: 269 AN: 1095994

Other (OTH) AF: 0.00278 AC: 165 AN: 59344

GnomAD4 genome AF: 0.00527 AC: 803 AN: 152348 Hom.: 8 Cov.: 33 AF XY: 0.00530 AC XY: 395 AN XY: 74498

African (AFR) AF: 0.0159 AC: 661 AN: 41582

American (AMR) AF: 0.00314 AC: 48 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 58 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68034

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00255 Hom.: 1

Bravo AF: 0.00595

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	2	Usher syndrome type 1D (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 12 (1)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.49
DANN	Benign	0.55
PhyloP100		-0.10
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs143136329; hg19: chr10-73492096;